Voxel-Based Imaging of Translocator Protein 18Kda (TSPO) in High-Resolution PET

In vivo imaging of translocator protein 18 kDa (TSPO) has received significant attention as potential biomarker of microglia activation. Several radioligands have been designed with improved properties. Our group recently developed an 18F-labeled TSPO ligand, [18F]-FEPPA, and confirmed its reliability with a 2-tissue compartment model. Here, we extended, in a group of healthy subjects, its suitability for use in voxel-based analysis with the newly proposed graphical analysis approach, Relative-Equilibrium-Gjedde-Patlak (REGP) plot. The REGP plot successfully replicated the total distribution volumes estimated by the 2-tissue compartment model. We also showed its proof-of-concept in a patient with possible meningioma showing increased [18F]-FEPPA total distribution volume.

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Quantification of Cerebral A1 Adenosine Receptors in Humans using [18F]CPFPX and PET

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000110531.48786.9d ◽

2004 ◽

Vol 24 (3) ◽

pp. 323-333 ◽

Cited By ~ 26

Author(s):

Philipp T Meyer ◽

Dirk Bier ◽

Marcus H Holschbach ◽

Christian Boy ◽

Ray A Olsson ◽

...

Keyword(s):

Compartment Model ◽

Graphical Analysis ◽

Attractive Alternative ◽

The Novel ◽

Tissue Compartment ◽

Arterial Blood ◽

Positron Emission ◽

Pet Scanning ◽

Kinetics Of

Adenosine is an important neuromodulator. Basic cerebral effects of adenosine are exerted by the A1 adenosine receptor (A1AR), which is accessible in vivo by the novel ligand [18F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ([18F]CPFPX) and positron emission tomography (PET). The present study investigates the applicability of kinetic models to describe the cerebral kinetics of [18F]CPFPX in order to quantify A1AR density in vivo. Six healthy volunteers underwent dynamic PET scanning and arterial blood sampling after bolus injection of [18F]CPFPX. For quantitative analysis, a standard two-tissue compartment model (2TCM) was compared with a one-tissue compartment model (1TCM) and Logan's graphical analysis (GA). The 2TCM described the cerebral kinetics of [18F]CPFPX significantly better than the 1TCM (in all regions and subjects examined). The estimated values of the regional total distribution volumes ( DVt) correlated strongly between the 2TCM and GA (linear regression r2 = 0.99, slope: 1.007). The DVt correlation between the 2TCM and the 1TCM was comparably high, but there was a significant bias towards lower DVt estimates given by the 1TCM (r2: 0.99, slope: 0.929). It is concluded that a 2TCM satisfactorily accounts for the cerebral kinetics of [18F]CPFPX. GA represents an attractive alternative method of analysis.

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Optimised GMP-compliant production of [18F]DPA-714 on the Trasis AllinOne module

EJNMMI Radiopharmacy and Chemistry ◽

10.1186/s41181-021-00133-0 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Klaudia A. Cybulska ◽

Vera Bloemers ◽

Lars R. Perk ◽

Peter Laverman

Keyword(s):

Significant Degree ◽

Translocator Protein ◽

Positron Emission ◽

Leaving Group ◽

Inflammatory Processes ◽

Single Production ◽

Translocator Protein 18 Kda ◽

Radiochemical Yields ◽

Specific Ligand

Abstract Background The translocator protein 18 kDa is recognised as an important biomarker for neuroinflammation due to its soaring expression in microglia. This process is common for various neurological disorders. DPA-714 is a potent TSPO-specific ligand which found its use in Positron Emission Tomography following substitution of fluorine-19 with fluorine-18, a positron-emitting radionuclide. [18F]DPA-714 enables visualisation of inflammatory processes in vivo non-invasively. Radiolabelling of this tracer is well described in literature, including validation for clinical use. Here, we report significant enhancements to the process which resulted in the design of a fully GMP-compliant robust synthesis of [18F]DPA-714 on a popular cassette-based system, Trasis AllinOne, boosting reliability, throughput, and introducing a significant degree of simplicity. Results [18F]DPA-714 was synthesised using the classic nucleophilic aliphatic substitution on a good leaving group, tosylate, with [18F]fluoride using tetraethylammonium bicarbonate in acetonitrile at 100∘C. The process was fully automated on a Trasis AllinOne synthesiser using an in-house designed cassette and sequence. With a relatively small precursor load of 4 mg, [18F]DPA-714 was obtained with consistently high radiochemical yields of 55-71% (n=6) and molar activities of 117-350 GBq/µmol at end of synthesis. With a single production batch, starting with 31-42 GBq of [18F]fluoride, between 13-20 GBq of the tracer can be produced, enabling multi-centre studies. Conclusion To the best of our knowledge, the process presented herein is the most efficient [18F]DPA-714 synthesis, with advantageous GMP compliance. The use of a Trasis AllinOne synthesiser increases reliability and allows rapid training of production staff.

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Novel Pyrazolo[1,5-a]pyrimidines as Translocator Protein 18 kDa (TSPO) Ligands: Synthesis, in Vitro Biological Evaluation, [18F]-Labeling, and in Vivo Neuroinflammation PET Images

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.5b00932 ◽

2015 ◽

Vol 58 (18) ◽

pp. 7449-7464 ◽

Cited By ~ 20

Author(s):

Annelaure Damont ◽

Vincent Médran-Navarrete ◽

Fanny Cacheux ◽

Bertrand Kuhnast ◽

Géraldine Pottier ◽

...

Keyword(s):

Biological Evaluation ◽

Translocator Protein ◽

Translocator Protein 18 Kda

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In vivo imaging of neuroinflammation in the rodent brain with [11C]SSR180575, a novel indoleacetamide radioligand of the translocator protein (18 kDa)

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-010-1628-5 ◽

2010 ◽

Vol 38 (3) ◽

pp. 509-514 ◽

Cited By ~ 36

Author(s):

Fabien Chauveau ◽

Hervé Boutin ◽

Nadja Van Camp ◽

Cyrille Thominiaux ◽

Philippe Hantraye ◽

...

Keyword(s):

In Vivo Imaging ◽

Translocator Protein ◽

Rodent Brain ◽

Translocator Protein 18 Kda

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Unbinding of Translocator Protein 18 kDa (TSPO) Ligands: From in Vitro Residence Time to in Vivo Efficacy via in Silico Simulations

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.9b00300 ◽

2019 ◽

Vol 10 (8) ◽

pp. 3805-3814 ◽

Cited By ~ 7

Author(s):

Agostino Bruno ◽

Elisabetta Barresi ◽

Nicola Simola ◽

Eleonora Da Pozzo ◽

Barbara Costa ◽

...

Keyword(s):

Residence Time ◽

In Silico ◽

Translocator Protein ◽

In Vivo Efficacy ◽

Translocator Protein 18 Kda

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TSPO PET Imaging: From Microglial Activation to Peripheral Sterile Inflammatory Diseases?

Contrast Media & Molecular Imaging ◽

10.1155/2017/6592139 ◽

2017 ◽

Vol 2017 ◽

pp. 1-17 ◽

Cited By ~ 9

Author(s):

Bérenger Largeau ◽

Anne-Claire Dupont ◽

Denis Guilloteau ◽

Maria-João Santiago-Ribeiro ◽

Nicolas Arlicot

Keyword(s):

Pet Imaging ◽

Inflammatory Diseases ◽

Protein A ◽

Translocator Protein ◽

Brain Diseases ◽

Disease Heterogeneity ◽

Peripheral Tissues ◽

Positron Emission ◽

Potential Biomarker

Peripheral sterile inflammatory diseases (PSIDs) are a heterogeneous group of disorders that gathers several chronic insults involving the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system and wherein inflammation is the cornerstone of the pathophysiology. In PSID, timely characterization and localization of inflammatoryfociare crucial for an adequate care for patients. In brain diseases,in vivopositron emission tomography (PET) exploration of inflammation has matured over the last 20 years, through the development of radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO) as molecular biomarkers of activated microglia. Recently, TSPO has been introduced as a possible molecular target for PSIDs PET imaging, making this protein a potential biomarker to address disease heterogeneity, to assist in patient stratification, and to contribute to predicting treatment response. In this review, we summarized the major research advances recently made in the field of TSPO PET imaging in PSIDs. Promising preliminary results have been reported in bowel, cardiovascular, and rheumatic inflammatory diseases, consolidated by preclinical studies. Limitations of TSPO PET imaging in PSIDs, regarding both its large expression in healthy peripheral tissues, unlike in central nervous system, and the production of peripheral radiolabeled metabolites, are also discussed, regarding their possible consequences on TSPO PET signal’s quantification.

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In vivo Evaluation of Inflammatory Bowel Disease with the Aid of μPET and the Translocator Protein 18 kDa Radioligand [18F]DPA-714

Molecular Imaging and Biology ◽

10.1007/s11307-014-0765-9 ◽

2014 ◽

Vol 17 (1) ◽

pp. 67-75 ◽

Cited By ~ 20

Author(s):

Nicholas Bernards ◽

Géraldine Pottier ◽

Benoit Thézé ◽

Frédéric Dollé ◽

Raphael Boisgard

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Translocator Protein ◽

In Vivo Evaluation ◽

Inflammatory Bowel ◽

Translocator Protein 18 Kda

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Quantification of Cerebral Nicotinic Acetylcholine Receptors by PET Using 2-[18F]Fluoro-A-85380 and the Multiinjection Approach

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600505 ◽

2007 ◽

Vol 28 (1) ◽

pp. 172-189 ◽

Cited By ~ 20

Author(s):

Jean-Dominique Gallezot ◽

Michel A Bottlaender ◽

Jacques Delforge ◽

Héric Valette ◽

Wadad Saba ◽

...

Keyword(s):

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Compartment Model ◽

Input Function ◽

Graphical Analysis ◽

Dissociation Rate ◽

Model Parameters ◽

Nicotinic Acetylcholine ◽

Arterial Blood

The multiinjection approach was used to study in vivo interactions between α4β2* nicotinic acetylcholine receptors and 2-[18F]fluoro-A-85380 in baboons. The ligand kinetics was modeled by the usual nonlinear compartment model composed of three compartments (arterial plasma, free and specifically bound ligand in tissue). Arterial blood samples were collected to generate a metabolite-corrected plasma input function. The experimental protocol, which consisted of three injections of labeled or unlabeled ligand, was aiming at identifying all parameters in one experiment. Various parameters, including B'max (the binding sites density) and Kd VR (the apparent in vivo affinity of 2-[18F]fluoro-A-85380) could then be estimated in thalamus and in several receptor-poor regions. B'max estimate was 3.0±0.3 pmol/mL in thalamus, and ranged from 0.25 to 1.58 pmol/ml_ in extrathalamic regions. Although Kd VR could be precisely estimated, the association and dissociation rate constants kon/ VR and koff could not be identified separately. A second protocol was then used to estimate koff more precisely in the thalamus. Having estimated all model parameters, we performed simulations of 2-[18F]fluoro-A-85380 kinetics to test equilibrium hypotheses underlying simplified approaches. These showed that a pseudo-equilibrium is quickly reached between the free and bound compartments, a favorable situation to apply Logan graphical analysis. In contrast, the pseudo-equilibrium between the plasma and free compartments is only reached after several hours. The ratio of radioligand concentration in these two compartments then overestimates the true equilibrium value, an unfavorable situation to estimate distribution volumes from late images after a bolus injection.

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Translocator Protein (18 kDa) Polymorphism (rs6971) Explains in-vivo Brain Binding Affinity of the PET Radioligand [18F]-FEPPA

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2012.46 ◽

2012 ◽

Vol 32 (6) ◽

pp. 968-972 ◽

Cited By ~ 79

Author(s):

Romina Mizrahi ◽

Pablo M Rusjan ◽

James Kennedy ◽

Bruce Pollock ◽

Benoit Mulsant ◽

...

Keyword(s):

Binding Affinity ◽

Microglial Activation ◽

Translocator Protein ◽

Time Activity ◽

Genetic Groups ◽

Positron Emission ◽

Translocator Protein 18 Kda ◽

Human Brains ◽

New Generation

[18F]-FEPPA binds to the 18-kDa translocator protein (TSPO) and is used in positron emission tomography (PET) to detect microglial activation. However, quantitative interpretations of the PET signal with new generation TSPO PET radioligands are confounded by large interindividual variability in binding affinity. This presents as a trimodal distribution, reflecting high-affinity binders (HABs), low-affinity binder (LAB), and mixed-affinity binders (MABs). Here, we show that one polymorphism (rs6971) located in exon 4 of the TSPO gene, which results in a nonconservative amino-acid substitution from alanine to threonine (Ala147Thr) in the TSPO protein, predicts [18F]-FEPPA total distribution volume in human brains. In addition, [18F]-FEPPA exhibits clearly different features in the shape of the time activity curves between genetic groups. Testing for the rs6971 polymorphism may allow quantitative interpretation of TSPO PET studies with new generation of TSPO PET radioligands.

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